Certain 5-substituted or unsubstituted phenyl or furyl benzofuran 2-carboxylic acids

ABSTRACT

6,7-Disubstituted-5-(acyl)benzofuran-2-carboxylic acids, the pharmaceutically acceptable salt, ester and amide derivatives thereof and combinations of these compounds with antikaluretic agents are disclosed having diuretic-saluretic, uricosuric and antihypertensive activity.

This is a division of application Ser. No. 733,840 filed Oct. 18, 1976now U.S. Pat. No. 4,085,117.

BACKGROUND OF THE INVENTION

This invention relates to certain benzofurans having diuretic-saluretic,uricosuric and antihypertensive pharmacological activity. Further, thisinvention relates to processes for the preparation of such compounds;pharmacological compositions comprising such compounds; and to methodsof treatment comprising administering such compounds and compositions topatients (both human and animal) for the alleviation of symptomsassociated with electrolyte imbalance and fluid retention such as edemaassociated with hypertension.

The compounds of this invention may be represented by the followinggeneric structure: ##STR1## wherein X is halo (chloro, fluoro, bromo oriodo) methyl or hydrogen;

Y is halo (chloro, fluoro, bromo or iodo) or methyl;

X and Y can be joined to form a hydrocarbylene chain containing from 3to 4 carbon atoms, for example: 1,3-butadienylene;

R is aryl such as phenyl or mono or disubstituted phenyl wherein thesubstituent(s) are halo, methyl, trifluoromethyl or methoxy; or aheterocyclic group such as a 5- or 6-membered heterocyclic ringcontaining one or more atoms of oxygen, sulfur or nitrogen such as 3- or2-thienyl, 2- or 3-furyl, 1,2,5-thiadiazolyl or substitutedheterocyclics as above wherein the substituent is halo or methyl.

Also within the scope of the present invention are the pharmaceuticallyacceptable salt, ester and amide derivatives of the above describedcompounds.

For convenience, these compounds will be collectively referred to as"benzofuran acids".

The pharmacological studies show that the instant products are effectivediuretic, saluretic and uricosuric agents which can be used in thetreatment of conditions associated with electrolyte and fluid retentionin the treatment of hypertension. These compounds are able to maintainthe uric acid concentration in the body at pretreatment levels or toeven effect a decrease in the uric acid concentration when administeredin therapeutic dosages in conventional vehicles.

Many of the presently available diuretics and saluretics have a tendencyupon administration to induce hyperuricemia which may precipitate uricacid or sodium urate or both in the body which may cause from mild tosevere cases of gout. The instant compounds of this invention nowprovide an effective tool to treat those patients (which includes humansand animals) requiring diuretic and saluretic treatment withoutincurring the risk of inducing gout. In fact, when used in appropriatedoses, the compounds of this invention function as uricosuric agents.

Thus, it is an object of the present invention to provide thebenzofurans of the above general description and to provide processesfor preparation of such compounds. Further objects of this invention areto provide pharmaceutical compositions comprising such benzofurans andto provide methods of treatment comprising administering such compoundsand compositions.

DETAILED DESCRIPTION OF THE INVENTION

For purposes of description, the benzofurans of the present invention(Formula I above) may be represented according to the followingstructural formula: ##STR2## wherein X, Y and R are as previouslydefined.

The preferred benzofurans of the present invention are those compoundsof Formula I wherein X is halo, preferably chloro, or methyl and Y ishalo, preferably chloro, or methyl, and the pharmaceutically acceptablesalts, ester and amide derivatives thereof.

More preferred benzofurans of the present invention are those preferredcompounds of Formula I wherein R is ##STR3## and X and Y are as definedabove.

Still more preferred benzofurans of the present invention are thosecompounds of Formula II below ##STR4## wherein X is chloro and

Y is chloro, and

R is as defined for the more preferred benzofurans above, and thepharmacologically acceptable salts, ester and amide derivatives thereof.

A still more preferred aspect of the invention are those compounds ofFormula II wherein X and Y are both chloro and R is ##STR5## and thepharmaceutically acceptable salts, ester and amide derivatives thereof.

Several examples of specific compounds of this invention are

6,7-Dichloro-5-(2-thenoyl)benzofuran-2-carboxylic acid;

6,7-Dichloro-5-(2-furoyl)benzofuran-2-carboxylic acid;

6,7-Dichloro-5-(5-methyl-2-thenoyl)benzofuran-2-carboxylic acid;

6,7-Dichloro-5-(3-thenoyl)benzofuran-2-carboxylic acid;

6,7-Dichloro-5-(3-furoyl)benzofuran-2-carboxylic acid;

6,7-Dichloro-5-(5-methyl-2-furoyl)benzofuran-2-carboxylic acid;

6,7-Dichloro-5-[3-(1,2,5-thiadiazolyl)]benzofuran-2-carboxylic acid;

6,7-Dichloro-5-p-methoxybenzoylbenzofuran-2-carboxylic acid;

The preferred groups of compounds depicted above have especially gooddiuretic, saluretic, uricosuric and antihypertensive pharmacologicalactivity.

The benzofurans of the present invention may be prepared essentially bythe reaction scheme shown below: ##STR6## wherein X, Y and R are asdefined, Z is halo and R² is lower alkyl (C₁₋₄).

In this reaction scheme, a 2,3-disubstituted-phenol (III) is treatedwith allyl bromide to yield the corresponding allyl ether (V). Typicallythe allyl bromide is employed in excess; in fact, it may serve as thereaction solvent. Other solvents, provided they are compatible with thedesired course of reaction may be employed, for example, ethanol,dimethylformamide and the like. Typically, the reaction is conducted inthe presence of a base such as sodium alkoxide, potassium carbonate andthe like at a temperature in the range of from about 25° to about 100°C. and is substantially complete in from about 0.5 to about 2 hours. TheClaisen rearrangement to obtain the 6-allyl compound (Formula VI) iseffected by heating the reaction mixture at from about 100° to 220° C.The benzofuran nucleus (VIII) is obtained from the 6-allyl compound (VI)by treatment with a peracid such as m-chloroperbenzoic, peracetic acidand the like in a solvent such as methylene chloride, chloroform, aceticacid and the like at a temperature of from about 0° C. to the refluxtemperature of the solvent wherein the epoxide (VII) which is initiallyformed cyclizes to (VIII). There are brackets around the epoxide ofFormula VII to indicate that it is most generally not isolated and is anintermediate in this particular reaction step. Oxidation of theresulting hydroxymethyl-substituted dihydrobenzofuran (VII) yields thedihydrobenzofurancarboxylic acid (IX).

Typically this oxidation is effected by oxidizing agents such as chromicacid, potassium permanganate and the like; the temperature of thereaction being typically in the range of from about 0° C. to the refluxtemperature of the solvent which is used.

The solvent can be any inert solvent that is not effected by thereaction.

The dihydrobenzofurancarboxylic acid compound (Formula IX) is convertedto the dihydrobenzofurancarboxylic acid intermediates (Formula X) byreacting said compound Formula IX or its lower alkyl (C₁₋₄) ester XIunder Friedel-Crafts conditions with a carboxylic acid halide of theformula: RCOZ wherein R has been previously defined and Z is halogensuch as chloro or bromo, to yield the desired intermediate. The loweralkyl ester XI and XII can be prepared from the acid IX and X by knownesterification procedures. Suitable catalysts for the Friedel-Craftstype reaction on compounds of Formula IX are aluminum chloride, tin (IV)tetrachloride and the like. The reaction solvent and temperature are notcritical inasmuch as any solvent which is inert to the acylhalide/dihydrobenzofuran reactants may be employed. In this regard,suitable solvents include aliphatic and cycloaliphatic hydrocarbons suchas heptane, cyclohexane, and the like; nitrohydrocarbons such asnitrobenzene and the like; and halogenated hydrocarbons such as carbontetrachloride methylene chloride, and the like are employable. Thereaction is generally run until formation of the desired product iscomplete, preferably from about 1 to 6 hours.

Typically the reaction is conducted from 0° C. to the reflux temperatureof the particular solvent employed but temperatures up to about 100°maximum may be employed. The 2,3-dihydrobenzofuran-2-carboxylic acidintermediates (Formula XII) are brominated with N-bromosuccinimide in aninert solvent such as carbon tetrachloride, methylene chloride and thelike at a temperature of 25° C. to the reflux temperature of the solventfor a period of from 1/2 to 4 hours. Evaporation of the solvent affordsa mixture of 2-bromo and 3-bromo dihydrobenzofuran-2-carboxylic acidester (Formula XIII).

Finally the mixture of 2 and 3-bromodihydrobenzofuran-2-carboxylic acidester is dehydrohalogenated by treatment with a dehydrohalogenatingagent such as a base, preferably an organic base such as1,5-diazabicyclo-(4.3.0)-5-nonene, 1,5-diazabicyclo-(5.4.0)-undec-5-ene,pyridine, lutidine, collidine, triethylamine and the like. The solventcan be an excess of the base being used or may be any other diluentwhich is substantially inert to the reactants such as dimethylsulfoxide,dimethylformamide and the like. The reaction may be conducted at atemperature of from about 0° to about 150° C. for a period of from about1 to about 8 hours; however, in most instances, the reaction isconveniently carried out at room temperature for a period of about 1hour to give the benzofuran-2-carboxylic acid ester (Formula XIV) whichupon hydrolysis affords the desired product, I.

As previously mentioned, the nontoxic, pharmacologically acceptablesalts of the acids of Formula I and II are within the scope of thisinvention. These salts include those of alkali metals, alkaline earthmetals and amines such as ammonia, primary and secondary amines andquaternary ammonium hydroxides. Especially preferred metal cations arethose derived from alkali metals, e.g., sodium, potassium, lithium, andthe like and alkaline earth metals, e.g., calcium, magnesium, and thelike and other metals, e.g., aluminum, iron and zinc.

Pharmaceutically acceptable salts can be formed from ammonia, primary,secondary, or tertiary amines, or quaternary ammonium hydroxides such asmethylamine, dimethylamine, trimethylamine, ethylamine,N-methylhexylamine, benzylamine, α-phenethylamine, ethylenediamine,piperidine, 1-methylpiperazine, morpholine, pyrrolidine,1,4-dimethylpiperazine, ethanolamine, diethanolamine, triethanolamine,tris(hydroxymethyl)aminomethane, N-methylglucamine, N-methylglucosamine,ephedrine, procaine, teramethylammonium hydroxide, tetraethylammoniumhydroxide, benzyltrimethylammonium hydroxide and the like. These saltsare particularly useful as parenteral solutions because they are verysoluble in pharmaceutical carriers such as water or alcohol.

Also included within the scope of this invention are the ester and amidederivatives of the instant products which are prepared by conventionalmethods well known to those skilled in the art. Thus, for example, theester derivative may be prepared by the reaction of abenzofuran-2-carboxylic acid of this invention with an alcohol, forexample, with a lower alkanol such as methanol or ethanol. The amidederivatives may be prepared by converting the same acid to itscorresponding acid chloride by treatment with thionyl chloride followedby treating said acid chloride with ammonia, an appropriate mono-loweralkylamine, di-lower alkyl amine or a hetero amine, such as piperidine,morpholine and the like, to produce the corresponding amide compound.These and other equivalent methods for the preparation of the ester andamide derivatives of the instant products will be apparent to one havingordinary skill in the art and to the extent that said derivatives areboth non-toxic and physiologically acceptable to the body system, saidderivatives are the functional equivalent of the corresponding freeacids of the present invention.

Of the non-toxic pharmaceutically acceptable salt, ester and amidederivatives of Formulae I and II, the preferred salts are those ofammonia, amines and of the alkali metals--principally sodium andpotassium; the preferred esters are those derived from lower alkanolshaving from 1 to about 6 carbon atoms; the preferred amides are thosederived from mono- and di-lower alkyl amines and hetero amines auch aspiperidine, morpholine and the like.

Although diuretics are often life-saving because of the above beneficialtherapeutic effects, most of them have the disadvantage of causing theexcretion of appreciable amounts of potassium ions. When an excessiveloss of potassium ions occurs, a severe muscular weakness and feeling ofextreme physical exhaustion results. The patient eliminates the unwantedsodium ions due to the action of the diuretic drugs but the undesiredelimination of the potassium ions produces an imbalance that should notbe allowed to persist.

This invention also involves co-administration of a benzofurancarboxylicacid with a pyrazinoylguanidine either in the form of a salt and/or as amixture with a hydrochloride salt of pyrazinoylguanidine, to therebyprevent the elimination of excessive amount of potassium ions withoutaltering or actually increasing the amount of sodium ions that areeliminated.

To achieve the beneficial results of this invention, the preferredpyrazinoylguanidine compound isN-amidino-3,5-diamino-6-chloropyrazinecarboxamide (amiloride) or itshydrochloride salt (amiloride hydrochloride) which is described in theliterature and patented arts.

Another advantage of theN-amidino-3,5-diamino-6-chloropyrazinecarboxamide salts of thebenzofurancarboxylic acid diuretics is their insolubility which makesthe salts' gastrointestinal absorption slower and more gradual providinga chemical method of achieving the same effect as microencapsulation.

The examples which follow illustrate the benzofuran products of thepresent invention and the methods by which they are prepared. However,the examples are illustrative only and it will be apparent to thosehaving ordinary skill in the art that all the products embraced by theabove-given description of the present invention may also be prepared inan analogous manner by substituting the appropriate starting materialsfor those set forth in the examples.

EXAMPLE 1 6,7-Dichloro-5-(2-thenoyl)benzofuran-2-carboxylic acid Step A:2,3-Dichloro-6-allylphenol

A mixture of 2,3-dichlorophenol (35.5 g., 0.22 mole), allyl bromide(29.4 g., 0.24 mole) and potassium carbonate (33 g., 0.24 mole) indimethylformamide (200 ml.) is vigorously stirred and heated at 55°-60°C. for one hour, poured into ice water, extracted with ether, washedwith water and dried over magnesium sulfate. Evaporation of the etherleaves 2,3-dichlorophenyl allyl ether which is subjected to a Claisenrearrangement by heating at 250° C. for ten minutes. Distillation gives36 g. of 2,3-dichloro-6-allylphenol which boils at 132°-4°/13 mm.

Elemental analysis for C₉ H₈ Cl₂ O; Calc.: C, 53.23; H, 3.97; Found: C,52.37; H, 3.86.

Step B: 6,7-Dichloro-2,3-dihydro-2-hydroxymethylbenzofuran

A stirred solution of sodium acetate (1 g.) in 40% peracetic acid (25ml.) is cooled to 15° C. then treated dropwise with2,3-dichloro-6-allylphenol. The reaction mixture is stirred at 25° C.for 48 hours, poured into excess aqueous sodium bicarbonate, extractedinto ether, washed with aqueous sodium bicarbonate, water, aqueousferrous sulfate, water, brine and dried over magnesium sulfate.Evaporation of the ether leaves 2,3-dichloro-6-(2,3-epoxypropyl)phenolwhich is rearranged by heating at 110° C. for ten minutes then distilledto give 10.4 g. of 6,7-dichloro-2,3-dihydro-2-hydroxymethylbenzofuranwhich boils at 130°/0.1 mm.

Elemental analysis for C₉ H₈ Cl₂ O₂ ; Calc: C, 49.34; H, 3.68; Found: C,49.67; H, 3.74.

Step C: 6,7-Dichloro-2,3-dihydrobenzofuran-2-carboxylic acid

To a solution of 6,7-dichloro-2,3-dihydro-2-hydroxymethylbenzofuran(10.4 gm.) in acetone (200 ml.) cooled to 20° C. is added an oxidizingsolution prepared from chromium trioxide (6.0 g.), concentrated sulfuricacid (5.3 ml.) and water (43 ml.) over a one-half hour period. Thereaction mixture is stirred at 25° C. for 18 hours. The acetone layer isseparated from the precipitated chromium salts, added to water (600 ml.)and extracted with ether (2×150 ml.). The ether extract is washed withwater then extracted with aqueous sodium bicarbonate. Acidification ofthe basic solution gives 3.4 g. of6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid which is purifiedby reprecipitation from aqueous sodium hydroxide with aqueoushydrochloric acid.

Elemental analysis for C₉ H₆ Cl₂ O₃ ; Calc.: C, 46.38; H, 2.60; Cl,30.43; Found: C, 46.38; H, 2.62; Cl, 30.29.

Step D: 6,7-Dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carboxylicacid

To a well stirred mixture of6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid (2.6 g.) andthiophene-2-carbonyl chloride (4 ml.) protected from the atmosphere witha calcium chloride tube is added anhydrous aluminum chloride (6.0 g.)over a one-hour period. The reaction mixture is heated at 80°-90° C. for31/2 hours then poured into ice water (100 ml.) and hydrochloric acid(10 ml.). The product is extracted into ether, washed with water, thenextracted into aqueous sodium bicarbonate (100 ml.) from which thesodium salt of the product precipitates. The sodium salt of the productis placed in a separatory funnel with dilute hydrochloric acid (100 ml.)and ether (100 ml.) and shaken until the solid dissolves. The ethersolution is washed with water, brine, dried over magnesium sulfate andthe ether distilled at reduced pressure. The6,7-dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carboxylic acid meltsat 187° C. after crystallization from butyl chloride.

Elemental analysis for C₁₄ H₈ Cl₂ O₄ S; Calc.: C, 49.00; H, 2.35; Found:C, 48.72; H, 2.56.

Step E: Methyl6,7-dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carboxylate

A solution of 6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid (3.4g., 0.01 mole) in methanol (50 ml.) containing conc. sulfuric acid (0.5ml.) is refluxed for one-half hour. The methanol is distilled at reducedpressure and the residual oil suspended in aqueous sodium bicarbonate(50 ml.) and extracted into ether (3×100 ml.), washed with brine anddried over magnesium sulfate. Filtration and evaporation gives 3.6 g. ofmethyl 6,7-dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carboxylatewhich is used in Step F without further purification.

Step F: Methyl 6,7-dichloro-5-(2-thenoyl)benzofuran-2-carboxylate

A solution of methyl6,7-dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carboxylate (3.6 g.,0.01 mole) in carbon tetrachloride (100 ml.) containing a few crystalsof benzoyl peroxide is treated with N-bromosuccinimide (1.8 g., 0.01mole) then refluxed for one hour. The reaction mixture is cooled,filtered free of succinimide and the solvent distilled at reducedpressure to leave a yellow residual oil comprised of a mixture of methyl2(and 3)-bromo-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylate which isdissolved in dimethylsulfoxide (25 ml.) treated with1,5-diazobicyclo(4.3.0)-5-nonene (1.3 g., 0.01 mole), stirred at 25° C.for two hours in an inert atmosphere, diluted with water (100 ml.) andacidified with hydrochloric acid to give methyl6,7-dichloro-5-(2-thenoyl)benzofuran-2-carboxylate which melts at184°-7° C. after recrystallization from acetonitrile-H₂ O.

Elemental analysis for C₁₅ H₈ Cl₂ O₄ ; Calc.: C, 50.72; H, 2.27; Found:C, 50.85; H, 2.43.

Step G: 6,7-Dichloro-5-(2-thenoyl)benzofuran-2-carboxylic acid

A solution of methyl 6,7-dichloro-5-(2-thenoyl)benzofuran-2-carboxylatein dioxane (50 ml.) containing 1 N sodium hydroxide (10 ml.) is refluxed2 hours and evaporated to dryness. The sodium salt thus obtained isshaken with 6 N hydrochloric acid (50 ml.) and ether (3×100 ml.). Theether extracts are combined, washed with brine, dried over magnesiumsulfate and distilled at reduced pressure to give6,7-dichloro-5-(2-thenoyl)benzofuran-2-carboxylic acid which melts at243°-5° C. after crystallization from acetonitrile.

Elemental analysis for C₁₄ H₆ Cl₂ O₄ ; Calc. C, 49.28; H, 1.77; Found:C, 49.01; H, 2.10.

EXAMPLE 2 Step A:6,7-Dichloro-2,3-dihydro-5-(2-furoyl)-benzofuran-2-carboxylic acid

To a well stirred mixture of6,7-dichloro-2,3-dihydro-benzofuran-2-carboxylic acid (3.3 g.),furan-2-carbonyl-chlorine (3.6 g.) and 200 ml. methylene chloride,protected from the atmosphere with a calcium chloride tube is addedanhydrous aluminum chloride (3.7 g.) over a one-half hour period. Thereaction solution is stirred 18 hours at 25° C. and then refluxed for 1hour. The solvent is removed and the residue added to ice water (200ml.) and hydrochloric acid (20 ml.). The product is extracted intoether, washed with water, then extracted into aqueous sodium bicarbonate(200 ml.) from which the sodium salt of the product precipitates. Thesodium salt of the product is placed in a separatory funnel with dilutehydrochloric acid (100 ml.) and ether (100 ml.) and shaken until thesolid dissolves. The ether solution is washed with water, brine, driedover magnesium sulfate and the ether distilled at reduced pressure. The6,7-dichloro-2,3-dihydro-5-(2-furoyl)-benzofuran-2-carboxylic acid meltsat 166° C. after crystallization from acetonitrile/n-butyl chloride.

Elemental analysis for C₁₄ H₈ Cl₂ O₅ ; Calc.: C, 51.40; H, 2.46 Found:C, 51.59; H, 2.72.

Step B: 6,7-Dichloro-5-(2-furoyl)benzofuran-2-carboxylic acid

By following substantially the procedure described in Example 1, Steps Ethrough G, there is obtained6,7-dichloro-5-(2-furoyl)benzofuran-2-carboxylic acid.

EXAMPLE 3 6,7-Dichloro-5-[3-(1,2,5-thiadiazolyl)]benzofuran-2-carboxylicacid Step A: 6,7-Dichloro-2,3-dihydrobenzofuran-2-carboxylic acid ethylester

A solution of 6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid (70g.) conc. sulfuric acid (2 ml.) and ethanol (250 ml.) is refluxed for 2hours. The ethanol is distilled at reduced pressure and the residue issuspended in saturated sodium bicarbonate and extracted with ether. Theether solution is washed with brine, dried over magnesium sulfate andthe ether distilled at reduced pressure. The6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid ethyl ester is usedwithout further purification in the following synthesis.

Step B:6,7-Dichloro-2,3-dihydro-5-[3-(1,2,5-thiadiazolyl)]benzofuran-2-carboxylicacid

To a well stirred mixture of6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid ethyl ester (17.5g.) and 1,2,5-thiadiazole-3-carbonyl chloride (21.7 g.) protected fromthe atmosphere with a calcium chloride tube is added the anhydrousaluminum chloride (29.4 g.) over a one-half hour period. The reactionmixture is heated at 90°-95° C. for 6 hours, then poured into ice water(400 ml.) and hydrochloric acid (40 ml.). The esterified product isextracted into ether, washed with water, dried over magnesium sulfateand the ether distilled at reduced pressure. The residue was warmed (80°C.) in 2.0 N NaOH (100 ml.) for one hour to obtain the insoluble sodiumsalt of the product. The sodium salt of the product is placed in aseparatory funnel with dilute hydrochloric acid (250 ml.) and ether (500ml.) and shaken until the solid dissolves. The ether solution is washedwith water, brine, dried over magnesium sulfate and the ether isdistilled at reduced pressure. The6,7-dichloro-2,3-dihydro-5[3-(1,2,5-thiadiazolyl)]benzofuran-2-carboxylicacid melts at 188° C. after recrystallization from acetonitrile.

Elemental analysis for C₁₂ H₆ Cl₂ N₂ O₄ S Calc.: C, 41.75; H, 1.75; N,8.12; Found: C, 41.77; H, 1.89, N, 8.06.

Step C: 6,7-Dichloro-5-[3-(1,2,5-thiadiazolyl)]benzofuran-2-carboxylicacid

By following substantially the procedure described in Example 1, Steps Ethrough G there is obtained6,7-dichloro-5-[3-(1,2,5-thiadiazolyl)]benzofuran-2-carboxylic acid.

EXAMPLE 4

Starting with 6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid butsubstituting equimolar amounts of the following acyl halides in place ofthiophene-2-carbonyl chloride in Step D of Example 1 and following theprocedure of Steps D through G there is obtained a corresponding amountof the appropriate end product listed.

    ______________________________________                                        ACID CHLORIDE   END PRODUCT                                                   ______________________________________                                        5-methylthiophene-2-                                                                          6,7-dichloro-5-(5-methyl-                                     carbonyl chloride                                                                             2-thenoyl)benzofuran-2-                                                       carboxylic acid                                               thiophene-3-carbonyl                                                                          6,7-dichloro-5-(3-thenoyl)-                                    chloride       benzofuran-2-carboxylic                                                       acid                                                          furan-3-carbonyl chloride                                                                     6,7-dichloro-5-(3-furoyl)-                                                    benzofuran-2-carboxylic                                                       acid                                                          5-methylfuran-2-carbonyl                                                                      6,7-dichloro-5-(5-methyl-                                      chloride       2-furoyl)benzofuran-2-                                                        carboxylic acid                                               ______________________________________                                    

EXAMPLE 5

Where in Example 1, Step D, there is substituted for the6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid an equivalentamount of 2,3-dihydro-6,7-dimethylbenzofuran-2-carboxylic acid,2,3-dihydro-6-methylbenzofuran-2-carboxylic acid,6-chloro-2,3-dihydrobenzofuran-2-carboxylic acid or6-chloro-2,3-dihydro-7-methylbenzofuran-2-carboxylic acid respectivelyand Steps E through G of Example 1 are performed, the followingcompounds of this invention are obtained, respectively:

6,7-dimethyl-5-(2-thenoyl)benzofuran-2-carboxylic acid;

6-methyl-5-(2-thenoyl)benzofuran-2-carboxylic acid;

6-chloro-5-(2-thenoyl)benzofuran-2-carboxylic acid;

6-chloro-7-methyl-5-(2-thenoyl)benzofuran-2-carboxylic acid.

EXAMPLE 6 6,7-Dichloro-5-(4-methoxybenzoyl)benzofuran-2-carboxylic acidStep A:6,7-Dichloro-2,3-dihydro-5(4-methoxybenzoyl)benzofuran-2-carboxylic acid

Following the procedure of Example 2 but using an equivalent amount ofanisoyl chloride in place of furan-2-carbonyl chloride used in Example2, there is produced an equivalent amount of6,7-dichloro-2,3-dihydro-5-(4-methoxybenzoyl)benzofuran-2-carboxylicacid., m.p. 187° C.

Elemental analysis for C₁₇ H₁₂ Cl₂ O₅ ; Calc.: C, 55.60; H, 3.29; Cl,19.31; Found: C, 55.67; H, 3.35; Cl, 18.99.

Step B: 6,7-dichloro-5-(4-methoxybenzoyl)benzofuran-2-carboxylic acid

By following substantially the procedure described in Example 1, Steps Ethrough G there is obtained6,7-dichloro-5-(4-methoxybenzoyl)benzofuran-2-carboxylic acid.

As mentioned previously, the novel compounds of this invention arediuretic and saluretic agents. When administered to patients intherapeutic dosages in conventional vehicles, the instant productseffectively reduce the amount of sodium and chloride ions in the body,lower dangerous excesses of fluid levels to acceptable levels and ingeneral, alleviate conditions usually associated with edema or fluidretention.

Also as mentioned previously, these compounds are able to maintain theuric acid concentration in the blood at pretreatment levels or evencause a decrease in uric acid concentration. The presence of excess uricacid in the blood can lead to crystallization of uric acid and uric acidsalts in the joints causing gout. In addition, hyperuricemia inconjunction with hyperlipidemia has been implicated in increasing therisk of sustaining cardiovascular heart disease.

The compounds of this invention can be administered to patients (bothanimal and human) in any of a variety of therapeutic dosages inconventional vehicles as, for example, by oral administration in theform of a tablet or by intravenous injection. In addition, the compoundsmay be formulated into suppositories or as a salve for topicaladministration or they may be administered sublingually. Also, the dailydosage of the products may be varied over a wide range as for example,in the form of scored tablets containing 0.25, 1, 5, 10, 25, 50, 100,150, 200, 250 and 500 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Thesedosages are well below the toxic or lethal dose of the products.

A suitable unit dosage form of the product of this invention can beadministered by mixing 25 mg. of a benzofuran or a suitable salt, esteror amide derivative thereof of the present invention with 174 mg. oflactose and 1 mg. of magnesium stearate and placing the 200 mg. mixtureinto a No. 1 gelatin capsule. Similarly by employing more of the activeingredient and less lactose, other dosage forms can be put up in No. 1gelatin capsules and should it be necessary to mix more than 200 mg. ofingredients together larger capsules may be employed. Compressedtablets, pills or other desired unit dosages can be prepared toincorporate the compounds of this invention by conventional methods andif desired can be made up as elixirs or as injectable solutions bymethods well known to pharmacists.

An effective amount of the product is ordinarily supplied at a unitdosage level of from about 0.003 mg. to about 10 mg./kg. of body weightof the patient. Preferably the range is from about 0.01 mg. to about 1.5mg./kg. with a most preferred dose being about 0.07 to 0.35 mg./kg. ofbody weight. The unit dose can be administered as infrequently as twiceper week to as frequently as 3 times per day.

It is also within the scope of this invention to combine two or more ofthe compounds of this invention into a unit dosage form or to combineone or more of the compounds of this invention with other knowndiuretics and saluretics or with other desired therapeutic and/ornutritive agents in dosge unit form.

The present invention embraces such compositions administration topatients, preferably by oral administration, wherein the potassiumconserving diuretic, N-amidino-3,5-diamino-6-chloropyrazinecarboxamidehydrochloride, hereinafter referred to as amiloride hydrochloride, ispresent as a physical mixture in combination with the benzofurans of thepresent invention. The present invention embraces compositions whereinthe molar ratio of the benzofuran to amiloride hydrochloride ranges fromabout 50:1 to 1:1. The preferred ratios of the benzofuran to amiloridehydrochloride ranges from 25:1 to 1:1.

EXAMPLE 7 Dry-filled capsules containing 50 mg. of active ingredientsper capsule

    ______________________________________                                                          Per Capsule                                                 ______________________________________                                        6,7-dichloro-5-(2-thenoyl)-                                                    benzofuran-2-carboxylic acid                                                                     50         mg.                                            Lactose             149        mg.                                            Magnesium stearate  1          mg.                                            Capsule (Size No. 1)                                                                              200        mg.                                            ______________________________________                                    

The 6,7-dichloro-5-(2-thenoyl)benzofuran-2-carboxylic acid is reduced toa No. 60 powder and then lactose and magnesium stearate are passedthrough a No. 60 bolting cloth onto the powder and the combinedingredients admixed for 10 minutes and then filled into a No. 1 drygelatin capsule.

Similar dry-filled capsules are prepared by replacing the activeingredient of the above example by the sodium, diethanolamine, andtriethanolamine salt thereof, respectively.

Similarly, dry filled capsules can be prepared by replacing the activeingredient of the above example by a molar equivalent amount of any ofthe other novel compounds of this invention.

What is claimed is:
 1. A compound having the formula: ##STR7## wherein X is halo, methyl or hydrogen;Y is halo or methyl and R is phenyl or mono or disubstituted phenyl wherein the substituent is halo, methyl, trifluoromethyl or methoxy; or furyl or substituted furyl wherein the substituent is halo or methyl, andthe non-toxic pharmaceutically acceptable salt or lower alkyl ester derivative thereof.
 2. A compound of claim 1 wherein X and Y are halo.
 3. A compound of the formula: ##STR8## wherein X is halo, methyl or hydrogen;Y is halo or methyl; R is selected from the group consisting of 2-furyl, 3-furyl, 5-methyl-2-furyl, phenyl, p-methoxy phenyl and p-chlorophenyl andthe non-toxic pharmaceutically acceptable salt or lower alkyl ester derivative thereof.
 4. The compound of claim 3 wherein X and Y are both chloro.
 5. A compound of claim 3 wherein X and Y are chloro and R is 2-furyl, 3-furyl or 5-methyl-2-furyl.
 6. The compound of claim 1 wherein X and Y are chloro and R is 2-furyl thus forming 6,7-dichloro-5-(2-furoyl)benzofuran-2-carboxylic acid.
 7. The compound of claim 1 wherein X and Y are chloro, and R is p-methoxyphenyl thus forming 6,7-dichloro-5-(p-methoxybenzoyl)benzofuran-2-carboxylic acid. 